This application for continuation of the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer at the Johns Hopkins University School of Medicine supports a highly interactive, multidisciplinary, and inter institutional program. Five research projects, three cores, a career development and a research developmental program are proposed to carry out our translational research in head and neck cancer. Research Project #1- Tumor Suppressor Gene Promoter Hypermethylation for Detection of Head and Neck Cancer - Co-Investigators, David Sidransky (basic) and Joseph Califano (clinic). Research Project #2 - Molecular Screening and Risk Prediction of HNSC. - Co-Investigators, William Westra (basic) and Wayne Koch (clinic). Research Project #3 - HPV Vaccine Therapy and Correlates of Response in Head and Neck Squamous Cell Carcinomas (HNSC) - Co-Investigators, TC Wu (basic) and Sara Pai (clinic). Research Project #4 - Combined Modality Treatment of Head and Neck Cancer Evaluating Inhibitors of the EGFR/TK Pathway - Co-Investigators, Manuel Hidalgo (basic) and Arlene Forastiere (clinic). Research Project #5 - Exploitation of RET Inhibitors for Treatment of Thyroid Cancer - Co-Investigators, Barry Nelkin (basic) and Doug Ball (clinic). The cores support the research programs (Core #1 - Pathology/ Tissue Core, Dr. Westra;and Core #2 - Administrative/Clinical Core (Drs. Sidransky &Forastiere), Core #3 - Biostatistics and Bioinformatics Core (Dr. Goodman). The Career Development Program (Dr. Forastiere) aids the emergence of new investigators and the Research Developmental Program (Dr. David Sidransky) provides rapid funding of innovative directions.